The present invention relates to transdermal drug delivery system (TDDS) of pharmaceutical compositions, which have a satisfactory in-vitro performance and good bioavailability. In particular, the transdermal pharmaceutical composition of clobazam in the present invention includes either liquid or semi solid in a reservoir patch dosage form or matrix or adhesive in a plaster dosage form for treatment of certain types of epilepsy and anxiety for 1 Day, 2 Day, 3 Day, 4 Day, 5 Day, 6 Day and/or 7-day continuous application.
Epilepsy is a group of neurological disorders characterized by epileptic seizures. These epileptic seizures are the result of excessive and abnormal cortical nerve cell activity in the brain, which causes episodes that can vary from brief and nearly undetectable to long periods of vigorous shaking. Lennox-Gastaut syndrome (LGS) is a form of severe epilepsy that begins in childhood. Multiple types of seizures and intellectual disability characterize it. The prognosis for individual with LGS varies. There is no cure for the disorder. Complete recovery, including freedom from seizures and normal development, is very unusual.
Lennox Gastaut Syndrome is one of the catastrophic childhood epilepsy syndromes, which is characterized by multiple seizure types including but not limited to tonic, atonic, atypical absence and generalized tonic-clonic seizures.
LGS develops during first decade of life, typically between 3-5 years of age and is common in males. The basic symptoms of it are multiple types of generalized seizures, difficult to control and/or slowness of intellectual growth such as mental retardation and behavioral problems.
The prevalence of LGS in developed countries was approximately 2 per 100,000 children and in Europe 0.1-0.28 per 1000. Studies demonstrated that the figure of LGS is relatively consistent across the developed populations. In Atlanta, USA, LGS accounts for 4% of patients with childhood epilepsy, with a reported incidence of 0.26 per 1000 live birth. (1)
Clobazam is a newer 1,5-benzodiazepine that is better tolerated and effective for all seizure types including drop attack for LGS. Clobazam is a benzodiazepine, which acts to enhance the actions of inhibitory neurons in the brain. This is accomplished by binding to certain sites on neuronal GABA-A1 receptors in a manner that enhances their efficacy. Since GABA is the principle inhibitory neurotransmitter in the brain, the actions of benzodiazepines are to reduce neuronal activity, reduce anxiety, promote sedation, and prevent the uncontrolled spread of neural excitation that result in epileptic seizures. Clobazam is class IV controlled substance because benzodiazepines can induce drug dependence.
Clobazam, has the structure

It is practically insoluble in water at 25° C., with solubility of 70 microgram/ml (μg/ml). Clobazam is used to treat CNS related disorders such as anxiety and epilepsy. The drug is currently sold as suspension and tablet form for oral administration.
Clobazam, in particular, has some disadvantages, which result from pharmacokinetic parameters when administered orally. Clobazam is subject first-pass liver metabolism. Due to this first-pass metabolism, clobazam causes gastro-intestinal side effects such as constipation, vomiting, problem swallowing, and change of appetite. To maintain a therapeutically effective plasma level, the patient has to take orally 5 mg or 10 mg dose everyday based on their body weight. Moreover, the highest dose of clobazam is 20 mg or 40 mg on the basis of patient body weight, which is divided in two or three times a day. In addition, it is very difficult to give medicine to the children orally, sometimes crushing of tablet(s) produce large particles due to untrained individuals, which may increase risk of aspiration or chocking. (3). Furthermore, by taking clobazam orally during school hours and/or social activities, children can be stigmatizing by other children, which adversely affect to their psychology behavior such as aggression, depression and insomnia. Clobazam can also produce infections such as upper respiratory tract infection, pneumonia, and bronchitis. Poor patient compliance with oral LGS has been reported.
As such, there exists a need for composition and methods of delivering antiepileptic drugs, such as clobazam, to improve patient compliance and maximize the pharmacological profile of the active agent. This need is met by the invention of a transdermal drug delivery system (TDDS) for systemic delivery of clobazam in a patch form. This system is able to deliver sufficient amounts of clobazam in vivo for therapeutic effects.
Clobazam is only 87% absorbed when taken orally. Clobazam is extensively metabolized by the liver through N-demethylation and Hydroxylation process. According to the invention, the TDDS releases clobazam onto the patient's skin, from a novel formulation that promotes the diffusion of clobazam through the skin so that it becomes systemically available. The rapid metabolism caused by the first pass effect duringoral administration is avoided. In addition, the TDDS, according to this invention ensures a constant delivery of the clobazam during an application period up to 7 days. In this way, the steady state plasma concentration can be maintained at a therapeutic level with a low frequency application. Delivering constant amount of clobazam through TDDS can compensate the short half-life of the clobazam. Furthermore, due to the transdermal administration, problems such as e.g. gastrointestinal intolerance, low enteral absorption or low per oral availability are eluded.
All references cited herein are incorporated herein by reference in their entireties.